Currently, pancreatic adenocarcinonna is the 4th leading cause of cancer death in the United States with a median survival of <6 month and a dismal 5-yr survival rate of 1-3%. The majority of patients diagnosed with pancreatic adenocarcinoma have disseminated disease at the time of diagnosis. Because clinical trials performed over the last 30 years also clearly demonstrated that only minimal progress has been made in patient survival, new strategies are desperately needed. The goal of this research is to develop a novel therapeutic approach using a metastasis suppressor to treat metastatic pancreatic adenocarcinoma and thereby improve patient survival. The metastasis suppressor, KiSS1, is a secreted protein that inhibits metastasis of human melanoma, breast, and ovarian cancer xenograft models. KiSSI expression levels are significantly lower in pancreatic cancer tissues from patients than normal pancreatic tissues. The hypothesis of this proposal is that metastasis of pancreatic adenocarcinoma can be significantly reduced (or prevented) by therapeutic strategies including KiSSI, a metastasis suppressor. Preliminary studies indicate that restoration of KiSSI greatly reduces both hepatic (97.5%) and pulmonary metastasis (99.4%) of pancreatic cancer in an orthotopic xenograft mouse model. Building upon these data, the proposed in vitro and in vivo experiments will evaluate the efficacy of KiSSI treatment alone, or combined with chemotherapy. Importantly, since KiSSI is a secreted, cytostatic protein, this strategy does not depend on restoration of KiSSI in all cancer cells. Rather, the effects of KiSSI are local, including via a by-stander effect, and systemic, due to secretion of KiSSI. Specific aim #1 will evaluate treatment of metastatic pancreatic cells transfected with KiSSI plasmid with chemotherapy in a xenograft mouse model. Aim #2 will address KiSSI delivery, and enable testing of KiSSI in a model system by producing a KiSSI-expressing adenovirus. Aim #3 will evaluate the treatment of metastatic tumors with the Ad-KiSS1 virusi Specific aim #4 will evaluate combination treatment with Ad-KiSS1 virus and chemotherapy in established metastatic and primary tumors in a xenograft model.